- Email: [email protected]
862 MiR-200 family: Critical suppressors of renal cell carcinoma proliferation and metastasis by modulating novel targets
Title
862
MiR-200 family: Critical suppressors of renal cell carcinoma proliferation and metastasis by modulating novel targets Eur Urol Suppl 2015;14/2;e862
Print! Print!
Zhang X., Chen X., Wang X., Ruan A., Han W., Shi H., Wang R., Chen L. Wuhan Union Hospital, Dept. of Urology, Wuhan, China INTRODUCTION & OBJECTIVES: Although microRNAs (miRNAs) have been revealed as crucial modulators of tumourigenesis, our understanding of their roles in renal cell carcinoma (RCC) is limited. Here we sought to identify miR-200 family that act as key regulators of renal carcinogenesis. MATERIAL & METHODS: We performed microarray-based miRNA profiling of clear cell RCC (ccRCC) and adjacent normal tissues and then explored the roles of miR-141 and miR-200c both in vitro and in vivo, which was the most significantly downregulated in ccRCC tissues. RESULTS: 74 miRNAs were dysregulated in ccRCC compared with normal tissues. Notably, four members (miR-141, 200b, 200c and 429) of miR-200s were all markedly reduced in ccRCC tissues. miR-141 and miR-200c was among the most remarkably downregulated miRNAs (about 100-fold) in ccRCC. miR-141 was remarkably downregulated in 92.6% (63/68) ccRCC tissues and would serve as a promising biomarker for discriminating ccRCC from normal tissues with an AUC of 0.93. Overexpression of miR-141 robustly impaired ccRCC cell migratory and invasive properties and suppressed cell proliferation by arresting cells at G 0 /G1 phase in vitro and in human RCC orthotopic xenografts. Significantly, the anti-tumour activities of miR-141 were mediated by its reversal regulation of EphA2, which then relayed a signaling transduction cascade to attenuate the functions of focal adhesion kinase (FAK), AKT, and MMP2/9. In addition, a specific and inverse correlation between miR-141 and EphA2 expression was obtained in human ccRCC samples. miR-200c was downregulated significantly in the tumour group with diameter more than or equal to 5 cm. Growth curve and FACS assay indicated that overexpression of miR-200c suppressed ccRCC cell growth and induced cell cycle arrest at G0/G1 phase. Furthermore, miR-200c could suppress tumour growth of SN12-PM6 cells in mice xenografts. Significantly, we demonstrated that Cyclin-dependent Kinase 2 (CDK2) was a novel functional target of miR-200c, which could directly suppress the protein expression of CDK2 in ccRCC cell lines and xenografts. CONCLUSIONS: miR-200 family (miR-141 and miR-200c), as crucial suppressors of ccRCC, attenuate tumour growth and metastasis by downregulating key oncogenes. Because our findings are based on clinical RCC samples and a good animal model, miR-200 family’s ability to suppress of tumourigenesis and metastasis may prove to be clinically useful.
file:///S|/IM/EURSUP/2015%20EAU%20Abstracts/content/data/862.html[19/02/2015 08:22:10]
862
MiR-200 family: Critical suppressors of renal cell carcinoma proliferation and metastasis by modulating novel targets Eur Urol Suppl 2015;14/2;e862
Print! Print!
Zhang X., Chen X., Wang X., Ruan A., Han W., Shi H., Wang R., Chen L. Wuhan Union Hospital, Dept. of Urology, Wuhan, China INTRODUCTION & OBJECTIVES: Although microRNAs (miRNAs) have been revealed as crucial modulators of tumourigenesis, our understanding of their roles in renal cell carcinoma (RCC) is limited. Here we sought to identify miR-200 family that act as key regulators of renal carcinogenesis. MATERIAL & METHODS: We performed microarray-based miRNA profiling of clear cell RCC (ccRCC) and adjacent normal tissues and then explored the roles of miR-141 and miR-200c both in vitro and in vivo, which was the most significantly downregulated in ccRCC tissues. RESULTS: 74 miRNAs were dysregulated in ccRCC compared with normal tissues. Notably, four members (miR-141, 200b, 200c and 429) of miR-200s were all markedly reduced in ccRCC tissues. miR-141 and miR-200c was among the most remarkably downregulated miRNAs (about 100-fold) in ccRCC. miR-141 was remarkably downregulated in 92.6% (63/68) ccRCC tissues and would serve as a promising biomarker for discriminating ccRCC from normal tissues with an AUC of 0.93. Overexpression of miR-141 robustly impaired ccRCC cell migratory and invasive properties and suppressed cell proliferation by arresting cells at G 0 /G1 phase in vitro and in human RCC orthotopic xenografts. Significantly, the anti-tumour activities of miR-141 were mediated by its reversal regulation of EphA2, which then relayed a signaling transduction cascade to attenuate the functions of focal adhesion kinase (FAK), AKT, and MMP2/9. In addition, a specific and inverse correlation between miR-141 and EphA2 expression was obtained in human ccRCC samples. miR-200c was downregulated significantly in the tumour group with diameter more than or equal to 5 cm. Growth curve and FACS assay indicated that overexpression of miR-200c suppressed ccRCC cell growth and induced cell cycle arrest at G0/G1 phase. Furthermore, miR-200c could suppress tumour growth of SN12-PM6 cells in mice xenografts. Significantly, we demonstrated that Cyclin-dependent Kinase 2 (CDK2) was a novel functional target of miR-200c, which could directly suppress the protein expression of CDK2 in ccRCC cell lines and xenografts. CONCLUSIONS: miR-200 family (miR-141 and miR-200c), as crucial suppressors of ccRCC, attenuate tumour growth and metastasis by downregulating key oncogenes. Because our findings are based on clinical RCC samples and a good animal model, miR-200 family’s ability to suppress of tumourigenesis and metastasis may prove to be clinically useful.
file:///S|/IM/EURSUP/2015%20EAU%20Abstracts/content/data/862.html[19/02/2015 08:22:10]